Diabetes - Hockerman Flashcards
Generic Name for Humalog
Insulin Lispro
Generic Name for Novolog
Insulin Aspart
Generic Name for Apidra
Insulin Glulisine
Generic Name for Lantus
Insulin Glargine
Generic Name for Levemir
Insulin Detemir
Generic Name for Tresiba
Insulin Degludec
List the VERY Rapid Onset/Short Action Insulins
Lispro, Aspart, Glulisine
humalog, novolog, apidra
List the rapid onset/short action insulins
Regular (R)
List the intermediate onset/action insulins
NPH (N)
List the slow onset/long action insulins
glargine, detemir, degludec
lantus, levemir, Tresiba
Describe “lente” insulins
insulin is complexed with Zinc to make an insoluble precipitate….
Explain NPH Insulin
Insulin is complexed with Protamine to delay absorption!
It is NOT genetically modified
Modification made to make Lispro Insulin?
lysine and proline switch positions on insulin B chain
P28 and K29
Modification made to make Aspart Insulin?
Proline 28 switched to aspartate
Modification made to make Glulisine Insulin?
Asn3 and Lys29 in B chain are switched to Lys and Glu
Modification made to make Glargine Insulin?
- Asn 21 of alpha chain is changed to Gly
- 2 Arg Residues added to end of beta-chain
Modification made to make Detemir Insulin?
Thr 30 of b chain is deleted - Lys 29 is myristylated (aka fatty acid added so it can bind to serum albumin extensively)
Modification made to make Degludec Insulin?
Thr 30 of b chain is replaced by Glu and fatty acid added (so it can bind to serum albumin)
(what is added “gamma-Glu/C16 fatty acid)
Examples of Mixture Insulins
NPH and Regular (Humulin 70/30 and 50/50)
NPL and Lispro (Humalog 75/25 & 50/50)
Ryzodeg (70% degludec and 30% aspart)
what is Afrezza?
inhaled insulin
Qualities that allow Afrezza to be inhaled?
large surface area and it is a small particle
4 routes of administration for insulin
SQ, Infusion Pump, IV, Inhalation
Uses of Insulins in Diabetics:
1) ________ liver glucose output
2) _________ fat storage
3) _________ glucose uptake
decrease; increase; increase
List Adverse Reactions to Insulin
- Hypoglycemia
- Lipodystrophy
- Lipoatrophy
- Insulin Resistance
Signs/Sx of hypoglycemia
weakness, sweating, hunger, tachycardia, increased irritability, tremor, blurred vision, seizures, coma, increased sympathetic output
Hypoglycemia = blood glucose is < ______
60 mg/dL
what is lipodystrophy?
lump of fat at over used injection site of insulin
what is lipoatrophy?
concavities in SQ tissue
Agents that can interact with Insulin/ cause an INCREASE in blood glucose
- catecholamines
- glucocorticoids
- Oral contraceptives
- thyroid hormone
- calcitonin
- somatropin
- isoniazid
- Phenothiazines
- morphine
Agents that increase the risk of insulin hypoglycemia
ETHANOL beta adrenergic receptors ACE inhibitors Fluoxetine Somatostatin Anabolic Steroids MAO Inhibitors
What Antidiabetic drugs will decrease glucose production
- Biguanides
- Insulin
What Antidiabetic drugs will decrease glucose absorption
- alpha-glucosidase inhibitors
- amylin mimetics
What Antidiabetic drugs will increase glucose excretion
SGLT2 inhibitors
What Antidiabetic drugs will increase glucose utilization
- thiazolidinediones
- insulin
What Antidiabetic drugs will increase insulin secretion
- sulphonylureas
- meglitinides
- GLP-1 Activators
- DPP-4 Inhibitors
type 1 or type 2 diabetes - which one uses antidiabetics
Type 2!
ADA Diagnosis Criteria: A1C Fasting Plasma Glucose 2-hours plasma glucose Random Plasma Glucose
> 6.5%; > 126 mg/dL; > 200 mg/dL; > 200 mg/dL
Type 1 diabetes - when beta cell mass is decreasing - is there positive or negative results for ICA and IAA
positive! (antibodies against ICA and IAA can cause
Pathophysiology of Diabetes:
Hyperglycemia seen when…
- _______ glucose uptake in cells where glucose uptake is insulin dependent
- _________ glycogen synthesis
- ________ conversion of amino acids to glucose
decreased; decreased; increased
Will see Hyperlipidemia in Diabetes because……
increased _________ and increased ________
fatty acid mobilization from fat cells; fatty acid oxidation (ketoacidosis)
Complications of Diabetes - Neuropathy:
increased blood glucose levels lead to increased utilization of the __________ (_________)
polyol pathway; Aldose Reductase;
Complications of Diabetes - Neuropathy:
Increased _________ in neural cells
cystosolic
Complications of Diabetes - Nephropathy:
what issues are present?
renal vascular changes and changes in the glomerular basement membrane
Complications of Diabetes - Ocular:
what can happen?
cataracts, retinal microaneurysms, hemorrhage
Ideal Ranges for Blood Glucose:
Fasting
70 - 90 mg/dL
Ideal Ranges for Blood Glucose:
Pre-Parandial
70 - 105 mg/dL
Ideal Ranges for Blood Glucose:
Post-Prandial
< 120 - 160 mg/dL
Acceptable Ranges for Blood Glucose:
Fasting
70 - 110 mg/dL
Acceptable Ranges for Blood Glucose:
Pre-Parandial
70 - 130 mg/dL
Acceptable Ranges for Blood Glucose:
Post meal
< 180 mg/dL
Insulin’s Effect on the Liver
Inhibits: Gluconeogenesis; Ketogenesis; Glycogenolysis
Stimulates: Glycogen Synthesis; Triglyceride Synthesis
Insulin’s Effect on the Skeletal Muscle
stimulates: glucose transport and amino acid transport
Insulin’s Effect on the Adipose Tissue
stimulates triglyceride storage and glucose transport
Insulin Receptor has 2 subunits
alpha and beta
role of the alpha subunit in the insulin receptor
it is a regulatory unit of the receptor - will represses activity of beta subunit - repression gets relieved by insulin
Insulin _______ is a clear solution at a pH of 4.0 - but when administered it will precipitate
glargine
Hypoglycemia S/Sx:
_______ sympathetic output
increased
How to treat hypoglycemia
glucagon/glucose
For the use of sulfonylureas - what MUST be functioning
beta cells
Sulfonylureas will help diabetics how? (affect glucose or insulin more directly?)
will increase release of insulin
Effects of Sulfonylureas on Beta Cell Insulin Release:
1) binds to _________
2) _______ K+ channel
3) _________ cell polarization
4) Activates ________ channels
5) Increases ______ and activity of _____
6) Increased exocytosis of ______ containing granules
sulfonylurea receptor; inhibits; decreases; voltage sensitive Ca2+; Ca2+; microfilaments; insulin
Does the drug increases or decrease blood glucose?
Catecholamines
increase
Does the drug increases or decrease blood glucose?
Glucocorticoids
increase
Does the drug increases or decrease blood glucose?
Oral Contraceptives
increase
Does the drug increases or decrease blood glucose?
thyroid hormone
increase
Does the drug increases or decrease blood glucose?
Calcitonin
increase
Does the drug increases or decrease blood glucose?
Somatropin
increase
Does the drug increases or decrease blood glucose?
Isoniazid
increase
Does the drug increases or decrease blood glucose?
Phenothiazines
increase
Does the drug increases or decrease blood glucose?
Morphine
increase
Does the drug increases or decrease blood glucose?
Ethanol
decrease
Does the drug increases or decrease blood glucose?
Beta-adrenergic blockers
decrease
Does the drug increases or decrease blood glucose?
ACE Inhibitors
decrease
Does the drug increases or decrease blood glucose?
Fluoxetine
decrease
Does the drug increases or decrease blood glucose?
Somatostatin
decrease
Does the drug increases or decrease blood glucose?
Anabolic steroids
decrease
Does the drug increases or decrease blood glucose?
MAO Inhibitors
decrease
What Classes of Antidiabetic Drugs Increase Insulin Secretion
- Sulphonylureas
- Meglitinides
- GLP-1 activators
- DPP-4 Inhibitors
What Classes of Antidiabetic Drugs decrease glucose absorption
- alpha-glucosidase inhibitors
- amylin mimetics
What Classes of Antidiabetic Drugs increase glucose excretion
SGLT2 inhibitors
What Classes of Antidiabetic Drugs decrease glucose production
- biguanides
- insulin
What Classes of Antidiabetic Drugs will increase glucose utilization
- thiazolidineodiones
- Insulin
Explain the Idea behind insulin being release from pancreatic beta cells
Glucose gets taken in by GLUT2;
Glucose encounters glucokinase –> G6P –> metabolism –> less ATP and more ADP
More ADP will close the K+ channel; causes depolarization; Ca2+ comes into cell; Ca2+ and microfilaments cause insulin granules to go to surface of cell and release insulin
which glucose transporter (GLUT#) has the HIGHEST Km
GLUT2
where is the highest Km GLUT# found?
beta cells (in pancreas)/liver
why does the pancreas and liver have a GLUT with such a high Km?
- high Km = more glucose needed to stimulate response - don’t want beta cells to pump out insulin for just little amounts of glucose…
which glucose transporter (GLUT#) is insulin induced
GLUT4
where is GLUT4 found?
skeletal muscle/adipocytes (GLUT4- insulin induced)
which glucose transporter (GLUT#) has the lowest Km, where is it found, and why
GLUT3; its in neurons; very low because you wants neurons/brain to be able to take in glucose even at low levels because you constantly need glucose for functioning
What types of cells are found in islet of langerhans
alpha, beta, delta
what cell in the islet of langerhan releases glucagon
alpha
what cell in the islet of langerhan releases somatostatin
Delta
what cell in the islet of langerhan releases insulin
beta
what cell in the islet of langerhan releases amylin
beta
beta cells in the islet of langerhan release what?
insulin AND amylin
alpha cells in the islet of langerhan release what?
glucagon
delta cells in the islet of langerhan release what?
somatostatin
what does Amylin do in the body?
- slows gastric emptying
- decreases food intake
- inhibits glucagon secretion
Insulin processing:
insulin is made in beta cells and is made as a ________ peptide that is deposited where?
single; secretory granules
In the secretory granule, insulin is cleaved into what two things
1) alpha/beta chain
2) C connecting peptide (C peptide)
List the sulfonylureas
1st gen (Tolbutamide, Chlorpropamide, Tolazamide)
2nd gen (glipizide, glimeperide, glyburide)
Sulfonylureas work intermittently or constitutively?
constitutively (can wear out the cells!!)
list the 2nd gen sulfonylureas
glipizide, glimeperide, glyburide
Main difference between 1st and 2nd gen of sulfonylureas?
potency
What drug class acts similarly to sulfonylureas but acts for a very short amount of time
Meglitinides (or the “glinides”)
Describe the qualities of the “glinide” antidiabetic drug class (Metiglinides)
- MOA: like sulfonylureas
- V SHORT DURATION OF ACTION (1 hr = half life)
- TAKE TABLET BEFORE EACH MEAL
how should/how often should glinides be taken
before each meal (bc short acting)
Examples of Glinides
Repaglinide, Nateglinide
which glinide is selective for K(ATP) channels in the pancreas, and not the hear?
Nateglinide
which glinide has a shorter half life?
Nateglinide (nate - works only at pancrease but v short half life)
ADE’s for Sulfonylureas
- lasting and prolonged hypoglycemia (b/c long af half life)
- G.I. problems
- Wt gain/
- INCREASED # of SECONDARY FAILURES
Drug Interactions for Sulfonylureas:
Which drugs may enhance the action of sulonylureas/increase risk of hypoglycemia due to the DISPLACEMENT of sulfonylureas from protein binding sites
- salicylates
- phenylbutazone
- sulfonamides
- clofibrate (Atromid S)
“types” of drug interactions for sulfonylureas
- may cause hypoglycemia (by displacing sulfonylureas from protein binding sites OR a drug has their own hypoglycemic effect and add as an additive)
- drugs cause hyperglycemia
what drugs can interact with sulfonylureas by having their own hypoglycemic effect
alcohol
high dose salicylates
what are some drug interactions that can oppose the action of sulfonylureas
- oral contraceptives
- corticosteroids
- epinephrine
- thyroid
- thiazide diuretics
why does oral glucose give a higher insulin release than IV glucose?
incretin effect
Idea behind “incretin effect”
peptide hormones (GIP and GLP-1) are released from the intestine after a meal - and go to islet of langerhans to stimulate beta cells
what peptide hormones are released from the small intestine that will be used to stimulate beta cells
Pro-GIP and PRO-glucagon (will become GLP-1)
Modes of Action for GLP-1:
_______ insulin secretion
stimulate
Modes of Action for GLP-1:
_________ glucagon secretion
suppress
Modes of Action for GLP-1:
________ gastric emptying
slows
Modes of Action for GLP-1:
_________ food intake
reduces
Modes of Action for GLP-1:
_________ beta cell mass and _______ beta cell function
increases; maintains
Modes of Action for GLP-1:
________ insulin sensitivity
improves
Modes of Action for GLP-1:
__________ glucose disposal
enhances
GLP-1 Receptor Signaling:
GLP-1 is a small peptide ______ (agonist, partial, antagonist) for _______ (what kind of receptor)
agonist; GPCR
GLP-1 Receptor Signaling:
Gs, Gq, and G(beta/gamma) pathways - will all (indirectly or directly) cause ________ (_____) which will cause increase in gene transcription and beta-cell proliferation
cause glucose-stimulated ERK1/2 phosphorylation (GSEP);
GLP-1 Receptor Signaling:
what pathways lead to GSIS (Glucose stimulated insulin secretion)
Gs and Gq
Recap on Signaling Pathways:
GPCR —> Gs —> ______ –> ______
AC; cAMP
Recap on Signaling Pathways:
GPCR —> Gq —> ______ –> ______
PLC; Ca2+
Recap on Signaling Pathways:
GPCR —> G(beta/gamma) —> ______ –> ______
PI3K; phosphorylation…
GLP-1 is secreted from ______ cells in the ______
“L”; intestine
GLP-1 levels may be ______ in T2DM
decreased!
How to combat low levels of GLP-1 in T2DM
- provide a long-lasting GLP-1 analog
- prevent degradation of endogenous GLP-1
Benefits of GLP-1 treatment for T2DM:
- _______ hyperglycemia with ____ risk of hypoglycemia
- _____ loss
- Increase _________
reduce; low; weight; beta cell mass
List the GLP-1 Analogs
- Exenatide (Exendin 4; Byetta)
- Victoza (Liraglutide)
- Tanzeum (Albiglutide)
- Dulaglutide (Trulicity)
- Lixisenatide (Adlyxin)
“tide-s”
What drugs are are inhibitors of DPP-4
-Gliptins!
(januvia, tradjenta, onglyza, Nesina)
(sitagliptin, linagliptin, saxagliptin, alogliptin)
DPP-4 inhibitors = GLP-1 _______
modulators
which DPP-4 inhibitor(s) are NOT extensively metabolized
januvia, nesina, tradjenta
which DPP-4 inhibitor(s) are extensively metabolized
onglyza (CYP3A4/5 substrate)
which DPP-4 inhibitor(s) are excreted in the urine (kidney)
Januvia, Nesina, Onglyza
which DPP-4 inhibitor(s) are excreted in the feces (liver)
Tradjenta
ADE’s of GLP-1 Modulators
N/V; Constipation; HA; SEVERE SKIN REACTIONS
DPP-4 is also present on _______ cells
immune
DPP-4 is on present cells:
leads to reduced ________ –> _______
Potential increased risk of _______
WBCs; infections; cancers
Amylin Analog name?
Symlin (Pramlintide)
Amylin Analog - useful in type 1 or type 2 or both?
both!
MOA of alpha-glucosidase inhibitors
decrease absorption of carbohydrates from the intestine by inhibiting gut alpha glucosidases
what enzymes does alpha-glucosidase inhibitors inhibit?
- sucrase
- maltase
- glucoamylase
What are some examples of alpha-glucosidase inhibitors
Acarbose and Miglitol
ADE’s for alpha-glucosidase inhibitors (and reasoning behind it)
diarrhea, nausea, flatulence (enzymes are not digesting it, so bacteria in gut DO digest it and leads to gas etc…)
Acarbose has risk of _____ damage when doses exceed _______
liver; 100 mg TID
what do SGLT2 inhibitor drug names end in…
-gliflozin
what are the drugs that are SGLT2 inhibitors
- jardiance
- invokana
- Farxiga
how do SGLT2 inhibitors work?
they work in the kidney - they decrease the reabsorption threshold for glucose in the kidney —- leads to more glucose being excreted into the urine (will decrease blood glucose levels!!)
are SGLT2 inhibitors for Type 1 , type 2 or both?
just type 2! should be used with diet/exercise
ADE’s for SGLT2 inhibitors
- increased risk of UTIs/genital infections (more sugar down there —- bacteria can grow better)
- increased urine flow/volume
- increased risk of hypoglycemia with sulphonylurea and insulin
what is the contraindication for SGLT2 inhibitors
pts with renal impairment!
which SGLT2 inhibitor should NOT be used in pts with BLADDER CANCER
Farxiga
Possible causes of insulin resistance
- polymorphisms in signaling pathways (rare)
- Obesity (accum. of fat in abdominal cavity)
- Inactivity
Effect of Insulin Resistance in Skeletal Muscle
- decreased glucose uptake
Effect of Insulin Resistance in Adipose Tissue
- impaired glucose uptake
- impaired inhibition of lipolysis
- mobilization of FAs to other tissues occurs
Effect of Insulin Resistance in the liver
impaired inhibition of glucose output (via gluconeogenesis and glycogenolysis)
Obese people - have ________ levels of free fatty acids
increased
_______ FFAs lead to Insulin Resistance (IR)
acutely raising
Insulin Resistance:
Polymorphism occurs how?
Ser gets phosphorylated (Tyr normally does!) this leads to inhibiting signaling
what things lead to polymorphisms of Insulin resistance/pathway signaling
promoted FA uptake, lipid-by products, inflammatory mediators (cytokines)
aka
Excess nutrients(like FFA), adpionectin, cytokines
Obesity Induced Inflammation and Insulin resistance:
_________ adipocytes are made by M1 infiltration
hypertrophied;
Obesity Induced Inflammation and Insulin resistance:
Hypertrophied adipocytes release what factors that will cause insulin resistance
- TNFa
- IL-6
- MCP-1
Obesity Induced Inflammation and Insulin resistance:
_______ from the hypertrophied adipocyte will decrease adiponectin
MCP-1
Obesity Induced Inflammation and Insulin resistance:
______ from hypertrophied adipocyte will go to monocyte
MCP-1
Obesity Induced Inflammation and Insulin resistance:
M# —> M# due hyperphagia and due to lack of exercise
2 –> 1
M1 is the hypertrophied adipocyte
Obesity Induced Inflammation and Insulin resistance:
what does MCP-1 stand for
monocyte chemoattractant protein - 1
Advantages of biguanide over sulfonylureas
- less chance of hypoglycemia
- rarely cause wt gain
Metformin has a lower risk of _______ compared to older biguanides
lactic acidosis
which drug is a part of the biguanide class?
metfomrin
MOA of Metformin:
is an activator of ________
AMPK (AMP-activated kinase)
MOA of Metformin:
increases efficiency/sensitivity of insulin where?
liver, fat, and muscle cells
Metformin’s Action in the Liver:
Metformin binds to _______
OCT1
Metformin’s Action in the Liver:
Metformin inhibits __________ at the mitochondria
oxidation at complex 1
Metformin’s Action in the Liver:
Inhibited oxidation of mitochondria leads to ________ levels of AMP
increased (bc not making ATP = more AMP)
Metformin’s Action in the Liver:
Inhibited oxidation of mitochondria leads to increased levels of ________
AMP
Metformin’s Action in the Liver:
High AMP levels will inhibit what process _________
gluconeogenesis (bc it inhibits Fructose bisphosphase (FBP))
remember ATP is needed for gluconeogenesis
Metformin’s Action in the Liver:
High AMP levels will increase/activate _______
AMPK
Metformin’s Action in the Liver:
High AMP levels will increase/activate AMPK which leads to _________
DECREASED lipid and cholesterol synthesis
where are the two main places that metformin affects
LIVER and SKELETAL MUSLCE
what does OCT stand for? (OCT 1 is the metformin receptor)
oragnic cation transporter
who is contraindicated for metformin
pts that have increased risk of lactic acidosis (ex: people w/ poor oxygenation - CHF pts…lung disease pts..)
Which drug leads to decreased abosorption of Vit. B12
metformin
Metformin leads to decreased absorption of _______
Vit. B12
Can metformin and sulfonylureas be used together?
yes!
Effect on lipid panel with metformin
- decreased serum LDL
- decreased TGs
How do thiazolidinediones decrease insulin resistance/improve target cell response
activates PPARy (PPAR gamma) aka a transcription factor
what does PPARy stand for
peroxisome proliferator activated receptor GAMMA
main target cells for thiazolidinediones
Adipocytes
how do thiazolidinediones affect Adipocytes
- enhance adipocyte differentiation
- enhance FFA uptake into SQ Fat
- reduce serum FFA
_____ FFA = less insulin resistance
less
Skeletal Muscles & Exercise:
______ accumulates during exercise and will activated ______
AMP; AMPK
more AMP b/c using ATP during exercise…duh
Skeletal Muscles & Exercise:
_____ phosphorylates TBC1D(1/4) which will promote ______ activity of _______
AMP; GTPase; Rab
Skeletal Muscles & Exercise:
Once Rab dissociates from ______ - it can translocate to the membrane
GLT4 (GLT4 will go to membrane)
How will metformin work in the skeletal muscle to increase insulin sensitivity?
metformin will increase AMPK
AMPK will phosphorylate TBC1D(1/4) - which increases GTPase activity of Rab - Rab comes off of GLUT4 - which allows GLUT4 to go to the membrane and bring in glucose!
what drugs are thiazolidinediones?
the “glitazone”s
- Pioglitzaone
- Rosiglitazone
(Remember pioglitzaone - looks like pig - pigs are fat - thiazolidinediones work on fat cells)
which thiazolidinediones is assoc. w/ increased risk of bladder cancer
Pioglitazone
Thiazolidinediones - can they cause hypoglycemia?
No!
what is the contraindication for thiazolidinediones?
CHF (b/c of fluid retention)
what are Adipokines
hormones that come adipose tissue
what type of adipokine can cause insulin dependent glucose upake
adiponectin
Structure and Function of PPAR-gamma:
PPAR has to bind to _____ - to make a _____ to regulate gene transcription
RXR; dimer
Structure and Function of PPAR-gamma:
List components of the structure of PPAR-y
Ligand independent activation domain; Ligand- dependent activation domain;
DNA binding domain
Ligand binding/Dimerization domain
List the factors that are regulated by activation of PPARy
- resistin
- adiponection
- TNF-a
- leptin
- angiotensinogen (AGE)
- plasminogen activator inhibitor (PAI-1)
what does leptin do in the body?
suppresses appetite; tells brain that the body is “fed”
PPARy is in control of releasing certain factors- all the factors are specifically released from
WAT - white adipose tissue
Is it low or elevated in Obesity/T2DM?
Leptin
???
Is it low or elevated in Obesity/T2DM?
Angiotensinogen
increased! — leads to HTN in obesity
Is it low or elevated in Obesity/T2DM?
PAI-1 (plasminogen activator inhibitor)
increased! — leads to increased risk of clots in obesity
Is it low or elevated in Obesity/T2DM?
Resistin
elevated
what does resistin do?
stimulates glucose export by liver
&
stimulates insulin resistance
what does adiponectin do?
decreases blood glucose and insulin resistance
what does TNF-a do?
stimulates lipolysis in WAT (white adipose tissue)
&
stimulates insulin resistance in skeletal muscle
when a TZD drug is given - what happens to levels of resistin
mRNA levels for resistin are DECREASED
when a TZD drug is given - what happens to levels of adiponectin
mRNA levels for adiponectin are INCREASED
when a TZD drug is given - what happens to levels of TNFa
mRNA levels for TNFa are DECREASED
Metformin or TZD?
molecular target is AMPK
metformin
Metformin or TZD?
molecular target is PPARy
TZD
Metformin or TZD?
pharmacologic action is to suppress HGP (hepatic glucose production)
metformin
Metformin or TZD?
pharmacologic action is enhanced insulin sensitivity
TZD
Metformin or TZD?
which one decreases A1c quite significantly
metformin!
Metformin or TZD?
which one reduces FFA quite significantly
TZD (bc they work on fat cells)
Metformin or TZD?
which one stimulates adiponectin quite significantly?
TZD
Metformin or TZD?
which on can cause wt gain
TZD
Metformin or TZD?
which one can cause peripheral edema
TZD
Metformin or TZD?
which one has increased risk of fracture and why/how
TZD; (TZD’s decrease differentiation of mesenchymal stem cells into osteoblasts!
